`
Research Article
Clinical Research and Trials
Clin Res Trials, 2021 doi: 10.15761/CRT.1000333
ISSN: 2059-0377
Volume 7: 1-5
Potential use of ivermectin for the treatment and prolaxis
of SARS-CoV-2 infection: Ecacy of ivermectin for
SARS-CoV-2
Cobos-Campos R
1
*, Apiñaniz A
1-3
, Parraza N
1
, Escudero J
1
, Bermúdez-Ampudia C
1
, Cordero J
1
, Sáez de Lafuente A
1
, García S
1
and Orruño E
1
1
Bioaraba Health Research Institute. Epidemiology and Public Health Research Group. Vitoria-Gasteiz, Spain
2
Osakidetza Basque Health Service. Aranbizkarra I Health Centre. Vitoria-Gasteiz, Spain
3
Department of Preventive Medicine and Public Health, EHU/UPV. Vitoria-Gasteiz, Spain
Abstract
Currently no treatment has been proven to be ecacious for patients with early or mild COVID-19. Although most patients present mild or moderate symptoms,
up to 5-10% may have a poor disease progression, so there is an urgent need for eective drugs, which can be administered even before the onset of severe symptoms,
i.e. when the course of the disease is more modiable. In addition to the antiparasitic eect of the drug, ivermectin also appears to possess an antibacterial eect, as
well as antiviral activity. is is the reason why it is thought that ivermectin could be also eective in the treatment and prophylaxis of SARS-CoV-2 infection, with a
good safety prole. e review of the scientic literature published to date seems to indicate that there is sucient evidence to recommend treatment with ivermectin
in patients with COVID-19 especially in the early stages of the disease.
*Correspondence to: Raquel Cobos Campos, Bioaraba Health Research Institute,
Isabel Orbe street w/n, 01002, Vitoria-Gasteiz, Spain, Tel: +34945207935; E-mail:
raquel.coboscampos@osakidetza.eus
Key words: Ivermectin, COVID-19, safety, ecacy, prophylaxis
Received: January 20, 2021; Accepted: January 27, 2021; Published: January 29,
2021
Introduction
Ivermectin is a macrocyclic lactone with a broad-spectrum
antiparasitic pharmacological activity [1]. It is the safest and most
eective semi-synthetic derivative of the entire avermectin class.
Marketed since 1981, its low cost, high ecacy and safety, and the
marked helminth tropism (therefore with almost no impact on human
biochemistry) have led to the inclusion of the drug in the 21
st
World
Health Organization List of Essential Medicines [2].
In addition to the antiparasitic eect, it also appears to have an
antibacterial eect [3], and antiviral and anticarcinogenic activity [4],
and it is particularly useful for treating certain chronic diseases [5].
Regarding the function as an antiviral agent, the ecacy has been
demonstrated against several viruses, both in vitro and in vivo. One
of the most important mechanisms by which ivermectin performs
its function, considers the drug an inhibitor of nuclear transport
mediated by the imported heterodimer α/β1, which is responsible for
the translocation of the proteins of several viral species (HIV-1, SV40),
and such translocation is in turn, essential for viral replication [6,7].
is inhibition appears to aect a considerable number of RNA viruses.
It has recently been shown that ivermectin inhibits the replication
of the SARS-CoV-2 virus in vitro [8,9], although it is not clear how
this occurs. However, since the causal agent of COVID-19 is an RNA
virus, the interference with the same proteins and molecular processes
described above can reasonably be expected. However, these studies
were conducted at concentrations substantially higher than expected
in the plasma and lungs of humans who receive the approved dose of
ivermectin. Pharmacokinetic and pharmacodynamic studies suggest
that in order to achieve the plasma concentrations required for in vitro
antiviral ecacy, it would be necessary to administer doses up to 100
times higher than those approved for human use [10,11]. However,
increasing the dose/kg of body weight may be a strategy to increase
ecacy, although the risk of toxicity may be increased [10].
Currently, there is a noteworthy absence of treatments proven to
be ecacious for patients with early or mild infection, so interventions
that can be administered early during the course of infection to prevent
disease progression and longer-term complications are urgently needed
[12]. Although most patients present mild or moderate symptoms, up
to 5-10% may have a bad disease progression, so there is an urgent
need for eective drugs [13], which can be administered even before
the appearance of severe symptoms, i.e. when the course of the disease
is more modiable. In fact, it is known that the earlier the antiviral
therapies are started, the greater the benets for patients, in both
inuenza [14] and SARS infections [15].
Given the need to nd an eective drug that can mitigate the
harmful consequences of COVID-19, a large number of studies are
being carried out in order to assess the eectiveness of dierent existing
drugs, including ivermectin, with promising results.
is narrative review summarizes and outlines the evidence-based
eectiveness and safety of ivermectin in patients with SARS-CoV-2
infection, recommending the drug for the treatment of COVID-19
specially in the early stages of the disease.
Cobos-Campos R (2021) Potential use of ivermectin for the treatment and prolaxis of SARS-CoV-2 infection: Ecacy of ivermectin for SARS-CoV-2
Volume 7: 2-5
Clin Res Trials, 2021 doi: 10.15761/CRT.1000333
Methodology
A literature search was conducted on MEDLINE, e Cochrane
Library and EMBASE databases with the following search strategy
"COVID-19 treatment" or "ivermectin treatment for COVID-19" or
"ivermectin treatment for SARS-CoV2 infection". No restrictions were
applied to the search. In order to identify unpublished studies, a search
was also conducted on clinical trial registration platforms such as,
Clinicaltrials.org.
In order to facilitate the review, the retrieved articles were organized
in the following four main topics: a) short-term ecacy in the treatment
of the disease, b) long-term ecacy in the treatment of patients with
post-acute symptoms of COVID-19, c) ecacy in the prophylaxis of
the disease, and nally, c) safety of ivermectin. e results of the studies
reviewed are presented as a narrative review.
Results
Short-term ecacy of ivermectin in the treatment of patients
with COVID-19
By short-term or early treatment of the disease, we refer to the
treatment administered immediately or soon aer symptoms appear.
Very recently, the WHO has commissioned a meta-analysis [16] to
assess the clinical ecacy of ivermectin through the ACC Accelerator
Program. e meta-analysis included 11 randomized controlled trials
(RCTs) conducted on a total of 1,452 RT-PCR positive patients (both,
inpatients and outpatients), with mild to severe COVID-19 symptoms.
e ecacy of ivermectin was assessed at doses of 200-600 µg/kg in a
1-7 day treatment schedule and an increase in survival of 83% (95%
Condence Interval (CI): 65%-92%) was observed in patients treated
with ivermectin, p<0.0001. Additionally, a reduction in hospital stay
from 18 days (standard deviation- SD 8) to 6 (SD 8) days, p<0.001, and
a reduction in the time for the negativization of PCR testing from 12
(SD 4) days to 6(SD 1) days p<0.001, in patients with no ivermectin
treatment and in patients treated with ivermectin, respectively,
were also calculated. Furthermore, the eect was shown to be dose
dependent, being greater for a 5-day pattern versus a single-dose
administration [16].
A real-time meta-analysis of 33 studies [17] conducted over a total
sample of 10,132 patients with COVID-19 disease, assessing 15 RCTs,
12 observational retrospective studies and 6 observational prospective
studies, described that all the studies included in the analysis reported
positive eects. According to the results of the meta-analysis, treatment
at an earlier stage of the disease (<=5 days aer the onset of symptoms)
is more successful, with an estimated 84% reduction in the measured
eects (fever, death, no virological cure, no resolution of symptoms,
need for ventilation, need for hospitalization, etc.) using a random-
eects meta-analysis, relative risk (RR) 0.16 [0.08-0.32] [17]. It should
be noted that, 100% of the 15 randomized controlled trials (RCTs)
included in the meta-analysis also report positive eects, with an
estimated reduction in the eect measure of 74%, RR 0.26 [0.15-0.47].
Generally, antiviral drugs are only considered eective when used at
the early stages of the infection, e.g., within 36-48 hours for oseltamivir,
with longer delays not being eective [18,19].
In another meta-analysis conducted by Mohan-Padhy, et al.
[20], which included 4 studies and a total of 629 COVID-19 RT-PCR
positive patients, to assess the therapeutic potential of ivermectin at
a standard dose of 200 µg/kg for the treatment of COVID-19 as an
adjuvant therapy to the standard care, an overall Odds Ratio (OR) of
0.53 (95% CI: 0.29 to 0.96) was reported for the primary outcome of all-
cause mortality which was statistically signicant (p=0.04) [20].
In a multicenter case-control study [21] of 280 hospitalized
patients, ivermectin administered in a single dose of 150 µg/kg to
patients diagnosed with SARS-CoV-2 infection, achieved a signicant
reduction in intrahospital mortality in those patients treated with the
drug (1.4% versus 8.5% (ivermectin versus non-ivermectin; Hazard
Ratio (HR) 0.20, 95% CI: 0.11 to 0.37, p<0.0001) [21]. ese results
are very similar to those obtained by Cepelowicz-Rajter, et al. [22],
in a retrospective study comparing the ecacy of two therapeutic
strategies (at least one dose of ivermectin + hydroxychloroquine and/
or azithromycin versus hydroxychloroquine and/or azithromycin). In
the group of patients who received ivermectin at a dose of 200 µg/kg, a
reduction in mortality was observed (15.0% versus 25.2%, OR 0.52, 95%
CI: 0.29 to 0.96, p=0.03). In the same study, the subgroup of patients
with severe lung disease showed an even lower mortality (38.8% versus
80.7%, OR 0.15, 95% CI: 0.05-0.47, p=0.001) [22].
In both studies described above, the standard dose was administered
(i.e., 150-200 µg/kg for most larial infections and S. stercoralis and
up to 400 µg/kg for Wuchereria bancroi infections) [23,24], which
contrasts with the very high doses of ivermectin employed in the in
vitro experiment conducted by Caly, et al. [8] with COVID-19-infected
cell lines, indicating that it appears that standard doses might also be
eective in reducing mortality.
In another interventional study conducted by Isho, et al. [25], in 30
hospitalized patients with mild to moderate COVID-19, no dierence
was observed in the percentage of cured patients among those
treated with 200 µg/kg in a single dose of ivermectin at the admission
day + hydroxychloroquine + azithromycin and those treated with
hydroxychloroquine + azithromycin, but there was a dierence in the
length of hospital stay (7.62 ± 2.75 versus 13.22 ± 5.90 days, p=0.00005)
and no adverse eects were observed [25].
Gómez-Hernández, et al. (26), observed in a retrospective cohort
of 325 patients diagnosed with SARS-CoV-2 infection, that disease
progression was better in patients treated with ivermectin at a single
dose of 12mg within 24-h aer hospital admission (lower incidence
of respiratory distress: 3 patients (2.5%) versus 21 patients (15.8%)
p<0.001) and lower need for intensive care: 1 patient (0.9%) versus
11 patients (8.3%) p<0.001) [26]. Furthermore, the length of hospital
stay was also lower in the group treated with ivermectin plus standard
care (9 (7-10) days) compared to standard care alone (15 (12-19) days)
(p<0.001) [26].
In another retrospective study that evaluated the mortality of 3,099
patients with a denitive or highly probable diagnosis of infection
due to COVID-19 (both inpatients and outpatients) treated with
ivermectin, a mortality-rate of 1.3% was found, which contrasts with
the world average mortality-rate of 2.2% [27]. Ivermectin dosage
varied depending on the type of patient; outpatients were administered
ivermectin at 400 µg/kg, orally in a single dose in the Emergency Service,
and azithromycin 500mg PO per day for 5 days, and hospitalized
patients were administered ivermectin orally at 300 µg/kg, at days 1
and 2, and the dose was repeated on days 6 and 7. Patients were given
azithromycin 500mg PO daily, for 7 days.
e routine prophylactic administration of ivermectin in Peru
starting from May 2020 was also associated with a reduction in
mortality due to SARS-CoV-2 [28]. Hashim, et al. in a randomized
controlled study conducted on 70 COVID-19 patients treated orally
Cobos-Campos R (2021) Potential use of ivermectin for the treatment and prolaxis of SARS-CoV-2 infection: Ecacy of ivermectin for SARS-CoV-2
Volume 7: 3-5
Clin Res Trials, 2021 doi: 10.15761/CRT.1000333
with 200ug/kg of ivermectin per day for 2-3 days along with 100mg of
oral doxycycline twice per day for 5-10 days in addition to the standard
therapy, also observed a reduction in recovery time and a reduction in
mortality in severe patients treated with doxycycline and ivermectin [29].
A non-randomized intervention evaluating the ecacy of
ivermectin combined with azithromycin and cholecalciferol treatment,
showed that the recovery-rate was 100% in patients treated with the
drug at the early stages of the disease [30].
e results of the clinical trial carried out by Chaccour, et al. [31],
in 24 patients who received a single dose of 400 µg/kg of ivermectin
or placebo, have recently been published. No dierence was found in
the proportion of patients with positive PCR at 7 days (RR 0.92, 95%
CI: 0.77 to 1.09, p = 1.0). Patients in the ivermectin group had fewer
days of symptoms as compared to those in the placebo group (171
versus 255 patient-days). e observed dierence was mainly due to
two symptoms, anosmia/hyposmia and cough. ere was no dierence
in the days of fever, malaise, headache, or nasal congestion between
the two groups. In contrast, the ivermectin group presented more days
of gastrointestinal symptoms (21 versus 6) and less days of respiratory
diculty (3 versus 15) [31].
Long-term ecacy of ivermectin in the treatment of patients
with post-acute symptoms of COVID-19
It is estimated that between 10 to 45% of people who become ill
with COVID-19 will present with symptoms aer the acute stage of
the disease [32]. In a study carried out by Aguirre, et al. 33 patients
with subacute symptoms of COVID-19 between weeks 4 and 12 from
the onset of symptoms, who received 2 consecutive daily doses of
ivermectin 200 - 400 µg/kg depending on the severity of the symptoms,
an improvement of symptoms (total or partial) was observed in 94%
of patients, and a total improvement in 87.9% of them. Patients whose
main symptoms were musculoskeletal, such as fatigue due to muscle
weakness, diminished muscle strength and myalgia (muscle pain)
were excluded from the study. If any symptoms were present aer the
second dose (12.1% of patients), 2 additional doses were administered,
reaching a 94% of success in the complete resolution of the symptoms
aer the fourth dose [32].
In another study carried out by the same authors, 21 adult patients
with persistent symptoms of anosmia or hyposmia received ivermectin
at a dose of 200 µg/kg of body weight per day for 2 days. If symptoms
did not disappear aer the second day of ivermectin treatment, patients
received two more doses of 400 µg/kg (in days 5 and 6). Among the
21 adult patients with persistent anosmia or hyposmia treated with
ivermectin, 66.7% had an overall clinical improvement aer the two
rst days of ivermectin treatment, and this percentage increased to
85.7% aer 2 more doses of ivermectin and acetylsalicylic acid for 5
days [33].
Ecacy of ivermectin for infection prophylaxis
e scientic literature provides evidence regarding the use of
ivermectin as a prophylactic agent. We searched for studies in which
the medication was regularly taken following dierent schedules in
order to prevent or minimize SARS-CoV-2 infection. We found a
real-time meta-analysis of 10 studies showing high eectiveness for
the prophylactic use of ivermectin, which reported a 90% reduction
in the risk of acquiring the disease on a sample of 3,663 patients RR
0.10 (0.04 to 0.23) [17]. e meta-analysis included 3 RCTs and 7
observational studies (4 retrospective and 3 prospective). e results
regarding prophylaxis remain very similar when only the three RCTs
included in the meta-analysis were taken into consideration, showing
a 91% reduction in the risk of a COVID-19 case (RR 0.09 (0.06 to
0.23)). Further, one of the studies included in the meta-analysis also
investigated the risk of death as the main outcome measure reporting a
99% improvement (RR 0.01 (0.00 to 0.10)) [34].
On the other hand, it has been observed that those countries with
prophylactic administration of drugs on a routine basis have less
incidence of COVID-19. us, a study conducted by Hellwig, et al.
collecting data from countries that use prophylactic drug therapy for the
treatment of other infections, detected a lower incidence of COVID-19
in patients treated with ivermectin at 150-200 µg/kg doses (p<0.05)
[35], without observing any remarkable dierence between doses. is
could be partly due to the relatively short half-life of ivermectin and the
little added eect of higher doses [36,37]. Additionally, the hypothesis
of activation of alternative routes when lower doses are employed
should be also considered [35].
In addition, it is interesting to note that the prophylactic
administration of ivermectin at a weekly single dose of 200 µg/kg up
to 8 weeks in 74 people (residents and workers in nursing homes)
produced IgG titers for SARS-CoV-2 of 5 to 10 times higher than the
standard titers in 85% of cases, showing that the workers included in
the study had come into contact with the virus, asymptomatically, but
their immune system was able to produce antibodies against SARS-
CoV-2 [38,39].
Safety
e safety of ivermectin at high doses (>400 µg/kg) appears to be
comparable to standard doses (<=400 µg/kg) according to a meta-
analysis of RCTs conducted by Navarro, et al. [39] (OR 1.16, 95% CI:
0.89 to 1.52). e severity of adverse reactions was similar in both
dosage groups and was mild or moderate in almost 100% of the cases.
Only one study reported a severe anaphylactic reaction in the standard
dose group and a prolongation of QTc (corrected QT interval) in the
high dose group [39]. Among the studies included in the meta-analysis
only one study on onchocerciasis (river blindness) treatment showed
an increase in eye reactions (transient blurred vision, itching, eye pain,
dyschromatopsia) (IR-incidence ratio 2.797, 95% CI 1.226 to 6.377)
[40]. ese observations are in agreement with the side eects reported
by other research groups [11,41,42].
In the clinical trial carried out by Chaccour, et al. [31], in which
12 patients were given a single dose of 400 µg/Kg of ivermectin and
12 patients were given a placebo, the patients in the ivermectin group
reported more patient-days of dizziness (7 versus 1) and blurred vision
(24 versus 1), although it should be taken into account that the blurred
vision was reported in a single patient [31].
Generally, ivermectin is well tolerated causing mainly dizziness,
nausea, headache, skin rash, and appears to be dose-dependent
[43,44]. Since the approval of the drug in the 1980s, the drug has
been distributed for the treatment of river blindness (onchocerciasis)
through the Mectizan program, administering more than 3 billion
treatments over the last 30 years, with an excellent safety prole. Most
adverse reactions are mild, transient and associated with the death of
the parasite rather than the drug itself [45]. Despite this, Chandler [46]
described a series of 28 cases with severe neurological reactions aer
ivermectin treatment outside the onchocerciasis-endemic areas. One of
the possible causes may be a variation of the MDR-1 gene, which may
have allowed ivermectin to penetrate the central nervous system [46].
Cobos-Campos R (2021) Potential use of ivermectin for the treatment and prolaxis of SARS-CoV-2 infection: Ecacy of ivermectin for SARS-CoV-2
Volume 7: 4-5
Clin Res Trials, 2021 doi: 10.15761/CRT.1000333
Ivermectin has anity for glutamate-gated chloride channels,
which are only present in invertebrates. Mammals only express a
similar channel that could potentially cross-react with ivermectin, but
such channels are only expressed in the central nervous system and
are protected by the blood-brain barrier thanks to the P glycoprotein,
a product of the MDR-1 gene, in humans [47]. is protein is located
in the endothelium of the brain capillaries and has the function of
eliminating substances or toxins found on the plasmatic membranes
before they penetrate the cell, or to eliminate toxic substances that have
managed to enter the cellular cytoplasm [48].
Discussion
e scientic evidence reviewed in this manuscript seems to clearly
indicate that ivermectin is eective in the short--term treatment and
prophylaxis of COVID-19. e debate now focuses on selecting an
eective dose with the best safety prole and lowest possible toxicity.
e doses used across the dierent studies reviewed range from 150-
800µg/kg, administered as a single dose or in a 1-7 days schedule.
According to the scientic evidence available, the standard dose (150-
400 µg/kg depending on the indication) could be eective and has a
lower probability of causing adverse reactions, especially at eye level
[45]. In relation to the dosing schedule, it appears that a multi-day
pattern would produce better results than the single dose [16].
It should be noted that the high quality evidence from meta-analyses
of randomized controlled trials [16] is also corroborated by other
studies (i.e., observational studies) reviewed in this article. Evidence
shows that non-RCT trials can also provide reliable results [49]. e
authors showed that the results of well-designed observational studies
(with either a cohort or a case–control design) do not systematically
overestimate the magnitude of the eects of treatment compared to
RCTs. So far, no individual clinical trial conducted to date is large
enough to clearly establish the ecacy of ivermectin for the treatment
of COVID-19. Nevertheless, the meta-analysis of 11 RCTs conducted
by Hills and colleagues [16] includes a sample of 1,452 patients with
COVID-19, providing stronger evidence on the ecacy of the drug. In
one month time, the results of two big RCTs will be available, which will
increase the pooled sample size to 3,000 patients, the same evidence-
base used for the approval of Remdesivir. Two possible limitations
should be also noted: rstly, that there is a possibility of publication
bias, by which only studies reporting positive results in relation to the
ivermectin treatment would be published and secondly, that several
clinical trials included in the meta-analysis are open-labelled and
therefore, the potential investigator bias cannot be ruled out.
With the available evidence, the Frontline COVID-19 Critical
Care Alliance (FLCCC) recommends the use of ivermectin in both
prophylaxis and treatment of COVID-19 [50]. It should be noted that
very recently the American NIH (National Institutes of Health) has
upgraded the recommendation and has issued a statement on the use of
ivermectin within the COVID-19 Treatment Guidelines [51]. Despite,
the NIH Guidelines do not recommend either for or against the use of
ivermectin for the treatment of COVID-19, they now allow treatment
of COVID-19 patients with ivermectin in the U.S.A. It should be noted
that the results of the recent systematic review of RCTs commissioned
by WHO have not been taken into consideration by the Guideline
Panel. e Health Ministries of India, Macedonia, Bulgaria and several
South American countries have already approved the use of ivermectin
for the treatment of COVID-19.
Several clinical trials are underway to further evaluate the ecacy
of ivermectin in the management of SARS-CoV-2 infection using
dierent dosing patterns. Further investigations should be conducted
in order to explore the above mentioned aspect, by means of carrying
out well-designed studies that would allow the assessment of the ecacy
and safety at low and high doses, following dierent dosing schedules.
Such studies should make a special emphasis on the incidence of ocular
and neurological adverse reactions and should also identify the prole
of patients where these adverse reactions occur most frequently.
Evidence regarding the eectiveness of ivermectin for the treatment
of persistent COVID-19 symptoms is provided by two prospective
observational studies conducted in 33 and 21 adult patients with post-
acute symptoms of COVID-19, respectively [32,33]. Nevertheless, it
is important to point out that the studies mentioned above have serious
methodological limitations. Firstly, both studies lack a control group
and have very small sample sizes. Secondly, the assessment of the main
outcome measures was subjective and has not been clearly specied in
the published papers. erefore, the evidence in favor of the treatment
with ivermectin for long-term COVID-19 is very weak due to the serious
limitations of the studies conducted by Aguirre-Chang and co-workers.
Given the high number of patients with persistent COVID-19 symptoms,
further investigations should be carried out in order to unequivocally
prove the eectiveness of ivermectin in long haulers. In this regard it is
crucially important to carry out well designed controlled clinical studies.
Given the signicant upsurge in cases of SARS-CoV-2 infection that
has occurred in recent months, the widespread use of ivermectin could
potentially play a crucial role in reducing in transmission-rates, as well
as decreasing short- and long-term morbidity and mortality in mild,
moderate and even severe phases of the disease [50]. In this regard,
it has been shown that treatment with ivermectin could produce IgG
titers for SARS-CoV-2 around 5 to 10 times higher as compared to the
titrations of untreated patients in 85% of people who had come into
contact with the virus asymptomatically [37,38].
Funding
None.
Conict of interest
Authors declare no conict of interest.
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